Aging causes physiologic changes in gastrointestinal intestinal function that contribute to many age-related disorders. The etiology of these disorders is likely multifactorial, but loss and degeneration of neurons in the enteric nervous system (ENS) likely plays a role. The proposed studies are predicated on the finding that age- associated cognitive decline is likely due to loss of neural stem cells related to central nervous system inflammation. While unknown whether a decline in enteric neural stem cells (ENSCs) contributes to loss of enteric neurons with aging, the discovery that ENSCs are involved in neurogenesis supports this interpretation. Interestingly, Foxo3, a transcription factor linked to longevity in humans was recently found to play a role in inflammatory disorders including Crohn's disease and Rheumatoid arthritis. Loss of Foxo3 signaling in myeloid cells was found to increase IL-6 production and drive inflammation. Based on preliminary data which found both a decline in Foxo3 expression and rise in proinflammatory cytokines in the ENS microenvironment with aging, it is posited that aging increases inflammation due to reduction in Foxo3 signaling in myeloid cells which in turn causes age-related ENS disturbances via a decline in functional ENSCs. This hypothesis will be addressed in two ways. First, the role of Foxo3 in age-dependent inflammation in the ENS will be examined. Specifically, the investigators will assess 1) whether inflammatory changes (with respect to inflammatory cytokines and immune cells) increase with aging in human and mouse tissue, 2) whether Foxo3 expression in myeloid cells declines with aging, and 3) if genetically induced Foxo3 deletion causes premature rise in inflammation with aging. Second, the investigators will examine whether modulation of Foxo3 mediates loss of functional ENSCs and neurons with aging. Specifically, the investigators will evaluate 1) if Foxo3 deficiency causes premature decline in functional ENSCs and enteric neuronal loss with aging and 2) whether Foxo3 deficiency particularly in immune cells is responsible for this decline. Successful completion of the proposed research will answer several key questions regarding the mechanism of age-related changes of the ENS including whether 1) inflammation plays a role in age-related disruption of the ENS in humans and mouse, 2) changes in Foxo3 signaling is responsible for age-dependent inflammation, and 3) inflammation causes loss of functional ENSCs thereby interfering with repair and rejuvenation of damaged tissue. This proposal will provide a proof of concept that immunomodulatory therapies have a role in age- associated gastrointestinal disorders.